Transplantation of organs or of bone marrow is common clinical practice for the cure of organ end failure or for recovery after bone marrow failure or depletion, respectively. Organs that can be transplanted include skin, kidney, liver, heart, lung, pancreas, intestine, cornea, and even hands or parts of the face. Cellular transplantation includes bone marrow and cord blood cells, but also cells such as those of the pancreatic Langerhans beta cell islets, hepatocytes and myoblasts. New technology has recently rendered it possible to graft stem cells that have been transformed in vitro by gene reprogrammation so as to adopt the differentiation pattern of virtually any cell. This very large diversity of situations in which transplantation is mandatory is likely to increase in the coming years, both because of technology advances and because of aging populations.
A cellular and organ transplant carried out between different individuals belonging to the same species is called an allograft or allotransplant. Alloreactivity describes an immune response to allograft transplantation that is directed towards allelic differences between a host (recipient) and a donor.
The mechanism of allograft rejection is based on the recognition of alloantigens. These can be divided in 3 main categories, namely major histocompatibility complex (MHC) antigens, minor histocompatibility antigens and organ-specific alloantigens. Allograft rejection involves the recognition by allograft recipient's T lymphocytes of such alloantigens presented in the context of MHC determinants, which are presented at the surface of antigen-presenting cells (APC) together with peptides derived from the processing of alloantigens.
MHCs are divided in two categories, class I and class II, encoded by different gene loci. In man, three loci encode antigens of class I, called A, B and C, and three loci encode for class II antigens, called DP, DQ and DR. The polymorphism of MHC antigens is very high, resulting in an extremely low likelihood to find 2 unrelated individuals sharing MHC antigens.
The function of MHC antigens is to present peptides to T cells. It is classically considered that class I antigens present peptides mainly derived from cell endogenous antigens, while class II antigens present peptides generated by the processing of antigens from the outside. Distinct pathways of processing and presentation at cell surface have been described for class I as compared to class II antigen presentation. However, recent data clearly indicate that endogenously produced antigens can be efficiently presented by the MHC class II pathway, whilst exogenous antigens can be processed via the class I pathway. Hence, any protein, whether of intracellular or extracellular origin is processed into peptides that are presented to T cells by both MHC class I and class II determinants.
Peptides presented by MHC class II determinants are recognized by T cells carrying the CD4 molecule (CD4+ T cells), whilst peptides presented by MHC class I determinants are recognized by CD8+ T cells. The mechanism by which T cells recognize peptides includes 3 possibilities. T cells can recognize the peptide itself, MHC determinants, or both the peptide and MHC determinants. Crystal structures of a number of peptide-MHC-TCR complexes have shown that in allorecognition, each of these recognition modes can be observed. However, recognition of MHC determinants does not exclude the presence of a peptide, required for the stabilization of the MHC molecule at the cell surface. In such a case, however, the peptide does not necessarily differ in its amino acid sequence from corresponding peptide from the graft recipient.
APC present at their surface a large number of antigens derived from the processing of endogenous antigens, including antigens of MHCs. Thus, class II antigens present peptides from both MHC class I and MHC class II molecules, which can be recognized by allospecific T cells. Class I and class II antigens are known to be shed from the donor cells or organs, which are taken up, processed and presented by recipient's APC for T cell recognition.
In addition to major MHC antigens, minor histocompatibility antigens have been defined on their capacity to elicit cell-mediated graft rejection, but lack the structural characteristics of MHC antigens. These minor antigens are processed into peptides and presented by MHC antigens. Rejection via minor histocompatibility antigens of the donor is dependent of the polymorphism of that antigen observed between individuals belonging to the same species, as, by definition, such individuals are tolerant to their own minor histocompatibility antigens. Such antigens can be expressed ubiquitously or in a tissue- or cell-selective manner. They include surface glycoproteins, but primarily intracellular antigens such as nuclear transcription factors. One of the best examples of minor histocompatibility antigens is the one provided by antigens encoded by the Y chromosome.
In man, the importance of minor histocompatibility antigens for rejection has mostly been observed in bone marrow acceptance and in graft versus host (GVH) reactions in which immunocompetent cells from the graft are activated towards antigens of the recipient. This is because the vast majority of bone marrow transplantations are carried out with complete MHC antigens match.
The third category of antigens are tissue-specific antigens. Such antigens can present allelic variations (i.e. polymorphism) between the donor and the recipient. Allopeptides derived from tissue-specific antigens can be presented by both MHC class II and MHC class I antigens for recognition by allospecific T cells.
The mechanisms at the basis of graft rejection are usually classified in two categories, direct or indirect allorecognition. The direct pathway involves the recognition of donor antigens presented by donor APC. The indirect pathway involves the recognition of donor antigens presented by APC of the recipient. This distinction applies for the three types of alloantigens described above and is important to bear in mind for two main reasons, namely the site at which these pathways are active and the kinetics of the rejection process.
The site at which these pathways are active is different. Donor's APC contained in the graft migrate to the recipient's regional lymph nodes where they stimulate recipient T cells. By contrast, recipient APCs infiltrate the graft where they progressively replace donor APC. The type of cells presenting the antigen is not necessarily the same. For example, in the skin, the main presenting cell is the Langerhans cell, whilst in lymph nodes it is primarily conventional dendritic cells.
The distinction between the direct and indirect pathways is also important in terms of the kinetics of rejection. Thus, acute rejection is mainly the result of the direct pathway, in which recipient T cells are activated by donor APC. Recipient T cells directly recognize allelic discrepancies resulting from the polymorphism of MHC molecules. The peptide presented by the MHC molecule may present allelic variations and can thereby contribute to T cell recognition, but this is not necessarily the case. Indeed, all MHC molecules contain hundreds of peptides, only some of which present allelic variations with corresponding peptides from the recipient.
The size of the T cell repertoire is such that a highly significant proportion of all T cells (up to 1 T cell out of 10,000) is capable of reacting towards MHC allelic variations, such that this mechanism predominates the acute rejection phase. In recipients presensitized to alloantigens by previous exposure via, for instance, blood infusion or pregnancy, allo specific antibodies can also participate to the acute rejection process. In some cases, minor histocompatibility determinants can also play a role in acute rejection via the direct pathway.
Acute rejection is reduced in the clinic by matching MHC antigens between the donor and the recipient, identifying pre-sensitized recipients and, in a large majority of cases, by suppressing the capacity of the recipient of rejecting the graft with immunosuppressive drugs.
The mechanisms at the basis of chronic graft rejection are multiple, but they can also be separated into direct and indirect mechanisms. However, in many situations, the indirect pathway predominates. This is due to the progressive disappearance of donor APCs that have migrated out of the graft and the fact that cells from the graft that express MCH class I molecules induce unresponsiveness of the receiver's T cells. One exception are cells from the vascular endothelium and epithelial cells, which, under inflammatory conditions can express MHC class II molecules and thereby have the capacity to activate allospecific T cells from the recipient.
The indirect pathway is generated by alloantigens which are shed from the graft and taken up by recipient APCs for presentation to recipient cells. These antigens generate peptides that are presented into either MHC class II or class I antigens. Recent experimental evidence has shown that presentation into MHC class II antigens is most important. Mice deficient in MHC class II antigens are not able to reject a graft of a minor histocompatibility antigen-disparate donor. In man, elimination of donor APCs from the graft does not prevent chronic rejection, whilst suppression of CD4+ T cell activation with immunosuppressors such as cyclosporine significantly reduces the incidence of chronic rejection.
A likely explanation for the predominance of MHC class II presentation in the indirect pathway of chronic graft rejection is that CD8+ T cells are not easily activated by recognition of allopeptides presented by MHC class I determinants, unless help is provided by CD4+ T cells. This most likely dependent of the production of interleukin 2 (IL-2) by CD4+ T cells, required for full maturation of CD8+ T cells.
T cells of the CD4+ subtype that recognize peptides within the context of MHC class II determinants have therefore different roles: production of IL-2 for CD8+ T cell maturation into effector T cells, production of cytokines helping B cells to mature into antibody-forming cells, and infiltration of the graft in which they maintain a state of inflammation.
Graft rejection, and in particular chronic graft rejection, nowadays represents the major challenge in the clinic. It results in significant morbidity and requires maintaining graft recipients under immunosuppressive therapy with many negative side effects. There is a need to identify methods for decreasing the rate of graft rejection. This would not only be to the benefit of patients having received a graft, but also to the whole society as the cost-benefit ratio for maintaining a healthy population could be reduced.